Desiccated Thyroid Extract Combined With Levothyroxine for TSH Suppression Therapy in DTC

Официальное название

Desiccated Thyroid Extract Combined With Levothyroxine for TSH Suppression Therapy in Intermediate-to-High Risk Differentiated Thyroid Cancer After Surgery: A National Multicenter, Open-Label, Randomized Controlled Trial

Обзор

The global incidence of Differentiated Thyroid Cancer (DTC) is rising. While surgery followed by TSH suppression is the standard of care, achieving target TSH levels with levothyroxine (L-T4) monotherapy remains challenging, with only 25-70% of intermediate/high-risk patients attaining it within 6-8 months. This therapeutic dilemma stems from three key issues: impaired T4-to-T3 conversion due to DIO2 polymorphisms, the non-physiological hormone ratio of T4 monotherapy, and L-T4's narrow therapeutic window. This often results in an "under- versus over-suppression" paradox, increasing risks of recurrence, atrial fibrillation, and osteoporosis. Combining L-T4 with desiccated thyroid extract (DTE; T4:T3 ≈ 4:1) may overcome these limitations by bypassing DIO2 defects and providing a more physiological hormone profile, thereby potentially improving TSH control while mitigating side effects. Supported by the 2023 Chinese guidelines and our promising pilot data (82% cumulative target attainment at a median of 1.4 months), we propose a two-stage national study: a multicenter cohort study followed by a randomized trial, to generate high-level evidence for this combination therapy in high-risk DTC.

Подробное описание

This study is a multicenter, open-label, randomized controlled trial. Stage 1 eligibility: (1) Age ≥ 18 years；(2) Histologically proven DTC after initial surgery (± ¹³¹I)；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) On L-T4 monotherapy: TSH above target despite FT4 ≥ 90 % of normal upper limit；(5) Signed informed consent and agreement to follow-up. Stage 2 eligibility: (1) Age 18-70 years (inclusive)；(2) Histologically proven DTC undergoing first-time surgery；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) Signed informed consent and agreement to post-operative follow-up. Exclusion criteria: (1) Non-DTC histology; (2) Hyperthyroidism, toxic adenoma, or toxic nodular goiter; (3) Malabsorptive GI disorders (e.g., H.-pylori gastritis, atrophic gastritis, celiac disease) or history of gastric bypass; (4) Hypersensitivity to levothyroxine or desiccated thyroid; (5) Angina, coronary artery disease, tachyarrhythmia, osteoporosis; (6) Concurrent malignancy; (7) Pregnant, lactating, or planning pregnancy within 12 months; (8) Severe COPD, hepatic or renal insufficiency, uncontrolled hypertension or diabetes, or any condition that could bias outcome assessment; (9) Chronic use of psychotropics, systemic glucocorticoids, amiodarone, chemotherapy, iron, thionamides, PPIs, or other drugs interfering with thyroid hormone; (10) Previous exposure to levothyroxine, desiccated thyroid, or T3 preparations; (11) Participation in another clinical trial that could interfere with this study.

Stage 1 prospectively enrolls patients who underwent initial DTC surgery at participating sites, were classified as intermediate or high recurrence risk, subsequently failed to achieve target TSH suppression on L-T4 monotherapy while having FT4 ≥ 90 % of the normal upper limit. The TSH-suppressive regimen is switched to DTE + L-T4, creating a before-and-after self-control study. Stage 2 screens patients scheduled for initial DTC surgery; eligible participants are randomized 1:1 to experimental arm (DTE + L-T4 combination) and control arm (L-T4). The stage 2 target sample size is 446 patients (223 per arm).

Data collection includes: (1) Baseline characteristics: sex, age, BMI, comorbidities (cardiovascular, endocrine, thyroid, etc.), prior neck irradiation; (2) Pre-operative imaging/labs: laryngoscopy, thyroid US, TSH, FT3, FT4, TT3, TT4; (3) Operative data: procedure type, date, extent of lymph-node dissection; (4) Symptom/QoL: ThyPRO-39 questionnaire; (5) hair-pull test for alopecia; (6) Genetics: DIO2 polymorphism; (6) Post-operative plan: initial TSH-suppression dose, first dosing date, RAI administration; (7) Pathology: histology, TNM stage, molecular results, ATA risk stratum. Follow-up at 1, 3, 6, 9, 12 months post-op and 1 month after every dose adjustment: (1) Vital signs, weight, TSH-suppression details; (2) Imaging/labs: thyroid US, TSH, FT3, FT4, TT3, TT4, Tg, TgAb, calcium, 25-OH-VD; (3) Adverse events: cardiovascular, musculoskeletal, neurologic, GI, allergic reactions; (4) ThyPRO-39 and hair-pull test repeated at each visit.

Вмешательства

• Препарат desiccated thyroid extract (DTE)+levothyroxine (L-T4)
  Desiccated thyroid extract (DTE) is a dry preparation obtained from animal thyroid glands that contains both thyroxine (T4) and triiodothyronine (T3) in an approximately 4:1 ratio, closely matching the physiological hormone profile secreted by the human thyroid. Combining DTE with levothyroxine (L-T4) may overcome current therapeutic bottlenecks. First, L-T4 given in adequate doses provides the major T4-mediated TSH suppression, while the small amount of T3 supplied by DTE acts directly on pitui

Первичные конечные точки

• Rate of adequate TSH suppression [Срок оценки: 1, 3, 6, 9, 12 months postoperative and 1 month after every dose adjustment]
• Time to TSH suppression target [Срок оценки: 1, 3, 6, 9, 12 months postoperative and 1 month after every dose adjustment]

Вторичные конечные точки (5)

• Thyroid function test [Срок оценки: Preoperative, 1, 3, 6, 9, 12 months postoperative and 1 month after every dose adjustment]
• Symptoms and quality of life related to thyroid dysfunction [Срок оценки: Preoperative, 1, 3, 6, 9, 12 months postoperative and 1 month after every dose adjustment]
• Assessment of hair-loss severity [Срок оценки: Preoperative, 1, 3, 6, 9, 12 months postoperative and 1 month after every dose adjustment]
• Adverse events (AEs) [Срок оценки: 1, 3, 6, 9, 12 months postoperative and 1 month after every dose adjustment]
• DIO2 polymorphism analysis [Срок оценки: Preoperative]

Критерии участия

Критерии включения

• Stage 1 eligibility: (1) Age ≥ 18 years；(2) Histologically proven DTC after initial surgery (± ¹³¹I)；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) On L-T4 monotherapy: TSH above target despite FT4 ≥ 90 % of normal upper limit；(5) Signed informed consent and agreement to follow-up. Stage 2 eligibility: (1) Age 18-70 years (inclusive)；(2) Histologically proven DTC undergoing first-time surgery；(3) ATA recurrence risk intermediate (low-intermediate or high-intermediate) or high；(4) Signed informed consent and agreement to post-operative follow-up.

Критерии исключения

• (1) Non-DTC histology; (2) Hyperthyroidism, toxic adenoma, or toxic nodular goiter; (3) Malabsorptive GI disorders (e.g., H.-pylori gastritis, atrophic gastritis, celiac disease) or history of gastric bypass; (4) Hypersensitivity to levothyroxine or desiccated thyroid; (5) Angina, coronary artery disease, tachyarrhythmia, osteoporosis; (6) Concurrent malignancy; (7) Pregnant, lactating, or planning pregnancy within 12 months; (8) Severe COPD, hepatic or renal insufficiency, uncontrolled hypertension or diabetes, or any condition that could bias outcome assessment; (9) Chronic use of psychotropics, systemic glucocorticoids, amiodarone, chemotherapy, iron, thionamides, PPIs, or other drugs interfering with thyroid hormone; (10) Previous exposure to levothyroxine, desiccated thyroid, or T3 preparations; (11) Participation in another clinical trial that could interfere with this study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• Turner, H.L., van Etten, J., Firth, D. et al. Modelling rankings in R: the PlackettLuce package. Computational Statistics.2020; 35(3): 1027-1057.
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• Hao D, Tian L, He H, Zhu C, Guo L, Zhang K, Zhang J. Efficacy and safety of postoperative levothyroxine sodium tablets for improving serum thyroid hormone levels and tumor marker levels in patients with thyroid tumors. Eur J Transl Myol. 2023 Sep 5;33(3):11582. doi: 10.4081/ejtm.2023.11582. PMID 37668013
• Wang Z, Angell TE, Sun W, Qin Y, He L, Dong W, Zhang D, Zhang T, Shao L, Lv C, Zhang P, Guan H, Zhang H. Analysis of the strategy of LT4 prescribing and TSH monitoring for thyroid carcinoma after lobectomy. Ann Transl Med. 2020 Oct;8(19):1238. doi: 10.21037/atm-20-4890. PMID 33178770
• Chen W, Li J, Peng S, Hong S, Xu H, Lin B, Liang X, Liu Y, Liang J, Zhang Z, Ye Y, Liu F, Lin C, Xiao H, Lv W. Association of Total Thyroidectomy or Thyroid Lobectomy With the Quality of Life in Patients With Differentiated Thyroid Cancer With Low to Intermediate Risk of Recurrence. JAMA Surg. 2022 Mar 1;157(3):200-209. doi: 10.1001/jamasurg.2021.6442. PMID 34935859
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• Yavuz DG, Yazan CD, Hekimsoy Z, Aydin K, Gokkaya N, Ersoy C, Akalin A, Topaloglu O, Aydogan BI, Dilekci ENA, Alphan Uc Z, Cansu GB, Ozsari L, Iyidir OT, Olgun ME, Keskin L, Mert M, Can B, Gungor K, Galip T, Canturk Z, Elbuken G, Pekkolay Z, Kutbay NO, Yorulmaz G, Kalkan AT, Unsal YA, Yay A, Karagun B, Bozkur E. Assesment of attainment of recommended TSH levels and levothyroxine compliance in diffe PMID 35639050
• Ku EJ, Yoo WS, Lee EK, Ahn HY, Woo SH, Hong JH, Chung HK, Park JW. Effect of TSH Suppression Therapy on Bone Mineral Density in Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2021 Nov 19;106(12):3655-3667. doi: 10.1210/clinem/dgab539. PMID 34302730

Идентификаторы

NCT: NCT07239674 · 2025(1862)

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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